Protecting Group-Free Synthesis

Use of In Situ Protections in Lieu of Short-Term Protecting Croups 

Follow Nature s Biogenetic Routes to Avoid Protecting Croups 

With reference to other situations in which protecting groups are commonly used, it takes more strategic considerations to render them dispensable. To develop some guidelines, it is appropriate to look again at Nature and to point out that Nature 

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Hoffmann, R.W. (2006) Protecting-Group-Free Synthesis. Synthesis, 3531-3541. 

Fig. 38 Examples of molecules prepared following new concepts in total synthesis (a) intricarene (220) generated by protective group-free synthesis and (b) late-stage site-selective C-H oxidations to generate eudesmane-type terpenes like 222 or (c) to prepare the hydroxylated artemisinin derivative 223...

Scheme 7.6 Protecting group-free synthesis of muscarine from 1957.

Scheme 7.10 In situ deprotonation of an interfering acidic group allowing an overall protecting group-free synthesis of hapalindole Q.

The spiraled architecture of welwitindolinone A isonitrile 196 has inspired the development of a variety of strategies for its construction. A beautifully simple protecting group-free synthesis of (-F)-welwitindolinone A has been achieved by Baran and coworkers [115-117]. As depicted in Scheme 48, the key step for installation of the aU-carbon quaternary center at oxindole C3 involved fluoro-hydroxylation of (—)-fischerindole 1 194 via treatment with aqueous Xep2. The desired natural product, 196, was obtained as a single diastereomer in 44% yield. The origin of the asymmetry at oxindole C3 can be traced back to enantiopure carvone oxide. 

Kim H, Nagald A, Yoshida J (2011) A flow-microreactor approach to protecting-group-free synthesis using organolithium compounds. Nat Commun 2 264... 

Hoffmann RW (2006) Protecting-group-free synthesis. Synthesis 3531—3541... 

The more reactive molybdenum catalyst 8.484 was employed to close the macrocyclic ring in the penultimate step of a protecting group free synthesis of Ecklonialactone A 8.498 (Scheme 8.133). ... 

Young, I. S., Baran, P. S. (2009). Protecting-group-free synthesis as an opportunity for invention. Nature Chemistry, 1, 193-205. 

Confronted with the need to develop a sustainable chemistry, we have witnessed an amazing increase in the efficiency and selectivity of synthetic methods in the last fifty years. In order to solve the problems associated with the traditional step-by-step procedures, such as the cumbersome, time-consuming, and expensive isolation of intermediates, several new criteria have been introduced atom, redox, step and pot economy or protecting-group-free synthesis. It is obvious that all variants of one-pot domino and cascade reactions or multicomponent consecutive reactions sequences may allow fulfilling these criteria. 

R.W. (2006) Synthesis, 21, 3531These papers contain very convincing recent examples of protecting-group-free synthesis and demonstrate the advantages of this strategy. 

This reductive Heck reaction has become a useful tool in cyclization reactions for complex molecule synthesis. In his protecting group free synthesis of ambiguine H (119), Baran successfully applied this strategy. Slow addition of Herrmann s catalyst 91 to substrate 117 provided intermediate 118 in a reliable 65% yield. This chemistry proved both robust and scalable, providing gram quantities of 118. 

Lee, Kiyoun Kim, Hyoungsu Hong, Jiyong. A Facile and Efficient Synthesis of 4-Hydroxy-2,6-c/i-tetrahydropyrans via Tandem Cross-Metathe-sis/Thermal Sn2 Reaction Protecting-Group-Free Synthesis of Diospongin A Org. Lett. 2009, 11, 5202-5205. 

Scheme 3.8 Protecting-group-free synthesis ( )-diospongin A...

SCHEME 13.15 Early examples of protecting-group-free synthesis. 

Protecting-Group-Free Synthesis Achieved by High-Resolution Reaction Time Control... 

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